Regulation of Skeletal Muscle Oxidative Capacity and Insulin Signaling by the Mitochondrial Rhomboid Protease PARL

Abstract

SUMMARY Type 2 diabetes Mellitus (T2DM) and aging are characterized by insulin resistance, lower mitochondrial density and function and increased production of reactive oxygen species (ROS). In lower organisms continuous remodeling critically maintains the function and life cycle of mitochondria, in part by the protease pcp1 (PARL ortholog). We therefore examined whether variation in PARL protein content is associated with mitochondrial abnormalities and insulin resistance. Relative to healthy, young individuals (23±1y), PARL mRNA and mitochondrial mass were both reduced in elderly subjects (64.4±1.2 y; 51% and 44% respectively) and in subjects with T2DM (51.8±3 y; 31% and 41% respectively; all p<0.05). Muscle knock-down of PARL in mice resulted in lower mitochondrial content (−31±3%, p<0.05), lower OPA1 and PGC1α protein levels and impaired insulin signaling. Furthermore, mitochondrial cristae were malformed and resulted in elevated in vivo oxidative stress. Adenoviral suppression of PARL protein in healthy myotubes lowered mitochondrial mass (−33±8%), insulin stimulated glycogen synthesis (−33±9%) and increased ROS production (2-fold) (all p<0.05). We propose that lower PARL expression may contribute to the mitochondrial abnormalities seen in aging and T2DM.

Intramembrane protease PARL defines a negative regulator of PINK1- and PARK2/Parkin-dependent mitophagy

“…Consistent with this, reduced mitochondrial mass has been reported upon muscle knockdown of PARL in mice 49 and expression of a cleavage-deficient PINK1 mutant in tissue culture cells. 30 Although signal sequences commonly target proteins only to one distinct cellular destination, dual targeting expands functionality of certain proteins.…”

Downregulation of mitochondrial lon protease impairs mitochondrial function and causes hepatic insulin resistance in human liver SK-HEP-1 cells

“…Recently, Civitarese et al reported that depletion of presenillin-associated rhomboid-like (PARL), a yeast mitochondrial protease purkinje cell protein 1 homologue, causes type 2 diabetes by inducing mitochondrial dysfunction. They showed that knockdown of PARL in muscle leads to mitochondrial dysfunction and subsequent impairment of insulin signalling through increased ROS generation; they also showed that the abundance of PARL was reduced in elderly and type 2 diabetes patients [32]. PARL is known as a mitochondrial processing peptidase located in mitochondrial inner membrane [7].…”

New roles for mitochondrial proteases in health, ageing and disease

“…SNPs in SPG7 are associated with several clinical phenotypes, including type 2 diabetes mellitus and coronary artery disease 143 . Likewise, defects in PARL have been linked to type 2 diabetes mellitus 144 . Mice that are deficient in OMA1 show a diet-induced obesity phenotype, with increased hepatic steatosis and alteration of glucose metabolism, in addition to defective thermogenesis 77,79 .…”